It is clear that opioid receptors play a role in the regulation of the immune response, including resistance to a number of infectious agents. The u- and K-opioids modulate the function of chemokine receptors which are critical both for normal immune responses, as well as for the host-parasite interactions associated with AIDS. In particular, the opioids regulate those chemokine receptors which serve as co-receptors for HIV-1. It appears that a major mechanism of this opioid-induced regulation involves a process termed "cross- desensitization." It is our hypothesis, based on our published results and preliminary data, that the cross- talk between opioid receptors and the major HIV-1 co-receptors, CCR5 and CXCR4, is responsible for altered susceptibility to infection by this virus. We propose three specific aims in this grant application. First, we propose studies to address the biochemical basis for the cross-desensitization of CCR5 and CXCR4 mediated by u-opioid and K-opioid receptors (MOR and KOR). Second, we intend to assess the influence of cross-desensitization between opioid and chemokine receptors on the physical arrangement and association of critical membrane proteins including CD4, CCR5, CXCR4, and opioid receptors. Finally, we propose to determine the biochemical basis for the altered susceptibility to HIV-1 infection associated with opioid- induced cross-desensitization of co-receptor function. We believe that these studies will clarify the nature of the influence of opioids, including opioid drugs of abuse, on HIV replication. In addition, we suggest that these studies will provide significant information regarding the regulation of essential receptors which control the generation of inflammatory responses in general. In particular, we expect that the proposed project will enhance our understanding of the role of certain drugs of abuse in the interaction of the immune system with HIV.